This PPT is part 1 of 2 lectures given to second year pharmacy students in a pharmacology & toxicology class.

1. Antidepressants I
Brian J. Piper, Ph.D., M.S.
January 25, 2013

2. Goals
• Major Depressive Disorder
• “Selective” Serotonin Reuptake Inhibitors (SRIs)
– pharmacodynamics
– adverse effects

3. Major Depressive Disorder
• Five + (1 or 2) causing significant social or
occupational impairment not due to medical
condition
– 1) Depressed mood most of the day, nearly every day
– 2) Marked diminished interest or pleasure, in activities
– 3) Significant weight loss/gain (+5%/month)
– 4) Insomnia/hypersomnia
– 5) Fatigue or loss of energy
– 6) Diminished ability to think or concentrate
– 7) recurrent thoughts of death, suicidal attempt/plan
No bereavement exclusion
Anna M. Kring, Ph.D. Lecture 14, 19:38-23:08

5. Hamilton Depression Inventory
http://www.psy-world.com/online_hamd.htm

6. Ham-D
Max Hamilton
1912-1988
Hamilton, M. (1967). Brit J Soc Clin Psychol, 6, 278-296.

7. Montgomery-Asberg Depression
Inventory
• 10 items x 6 points each
– 0-6: normal
– 7 to 19: mild depression
– 20 to 34: moderate depression
– 35 to 60: severe depression
• Response: total score reduced by >50%
• Partial Response: total score reduced by 25-49%
• Non-Response: total score reduced by 0 – 24%
Williams et al. (2008). British Journal of Psychiatry, 192(1), 52-58.

8. MDD Pathophysiology: Imbalance?
• MDD patients do not show measurable
deficits in 5-HT, norepinephrine, dopamine or
their metabolites
• MDD is not a simple “chemical imbalance”
• Avoid misinformation (even well intentioned)
≠
Serotonin & Depression (9 min): http://www.npr.org/blogs/health/2012/01/23/145525853/when-it-comes-to-depression-serotonin-isnt-the-whole-story

9. MDD Pathophysiology: Cortisol
• The Hypothalamus-Pituitary-Adrenal (HPA) axis
controls release of the stress hormone cortisol.
• As many as half of depressed patients show
elevations in cortisol. Drugs that turn off the HPA axis
are ineffective.
Belmaker & Agam (2008). New England Journal of Medicine, 358, 55-68.

10. General Adage
• “ … it is becoming more and more difficult to
prove that antidepressants – even well-
established antidepressants – actually work
any better than placebo in clinical trials.”
Stahl, S. (2008). Essential Psychopharmaology, p. 514.
Begley, S. (2/8/2010). Newsweek, 2/8/2010, 155(6). Stephen M. Stahl, M.D., Ph.D.

11. First Line Therapy
• Cognitive behavioral or interpersonal
psychotherapy are 1st for mild or moderate
depression
Severe-------------------
Moderate----------
Mild------------
Teter et al. (2011). In DiPiro Pharmacotherapy: A Pathophysiological Approach, p. 1177.

12. Monoamine (5-HT, NE, DA) Effects of
Antidepressants
Presynaptic Post-
synaptic
Stahl, S. (2008). Essential Psychopharmaology, p. 520.

13. Sequential Approach
Stahl, S. (2008). Essential Psychopharmacology, p. 517.

14. Simultaneous Approach
TCA: tricyclic; SNRIs: selective norepinephrine reuptake inhibitors; NaSSA:
noadrenergic & serotonin specific antidepressants

15. The (not so) Selective Serotonin
Reuptake Inhibitors
SRIs:
fluoxetine (Prozac)
sertraline (Zoloft)
paroxetine (Paxil) sexual side effects
fluvoxamine (Luvox)
citalopram (Celexa)
escitalopram (Lexapro) SRI: serotonin reuptake inhibitor
NRI: norepinephrine reuptake inhibitor
DRI: dopamine reuptake inhibitor
5-HT2C: serotonin 2C antagonist
m-ACh: muscarinic Acetylcholine
σ: sigma peptide
NOS: nitric oxide synthetase
Stahl, S. (2008). Essential Psychopharmaology, p. 531.

16. SSRIs & the dynamic 5-HT System
• A) block SERT
5-HT1-7
Stahl, S. (2008). Essential Psychopharmacology, p. 526.

17. SSRIs & the dynamic 5-HT System
• A) block SERT
• B) down-regulate auto-receptor (5-HT1A)
→
Stahl, S. (2008). Essential Psychopharmacology, p. 527.

18. SSRIs & the dynamic 5-HT System
• A) block SERT
• B) down-regulate auto-receptor (5-HT1A)
• C) increased 5-HT release
Stahl, S. (2008). Essential Psychopharmacology, p. 528.

19. SSRIs & the dynamic 5-HT System
• A) block SERT
• B) down-regulate auto-receptor (5-HT1A)
• C) increased 5-HT release
• D) down-regulate post-synaptic
receptors
Stahl, S. (2008). Essential Psychopharmacology, p. 528.

20. Fluoxetine
• 5-HT-Catecholamine Crosstalk
– 5-HT2C Agonist: ↓NE/DA
– 5-HT2C Antagonist: ↑NE/DA
• FDA approved for:
– Major Depression (Adults)
– Major Depression (Children)
• Half-life
– Fluoxetine: 3 days
– Norfluoxetine: 2 weeks
Stahl, S. (2008). Essential Psychopharmaology, p. 531.

21. Consequences of 2D6 Inhibition
Wilens et al. (2002). Journal of Clinical Psychopharmacology, 22(2), 169-173.

22. Other SRIs
sertraline escitalopram
• 2nd best selling • most selective of SRIs
antidepressant

23. x
Stahl, S. (2008). Essential Psychopharmacology, p. 490.

24. FDA Warning (2004)
• “Antidepressants increased the risk of suicidal thinking
and behavior (suicidality) in short-term studies in
children and adolescents with MDD and other
psychiatric disorders. Anyone considering the use of
___________ or any other antidepressant in a child or
adolescent must balance this risk with the clinical
need. Patients who are started on therapy should be
observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers
should be advised of the need for close observation
and communication with the prescriber. ”

25. Adults too!
Suicides: Drug = 5.2 /10,000; Placebo = 2.0/10,000; 2.6 fold
Attempted Suicide: 3.7 / 1,000; Placebo = 1.6/1,000; 2.3 fold
Healey, D. (2009). Canadian Journal of Psychiatry, 54(2),69-71.